Title: The Role of Olfactomedin 4 in Septic Shock Abstract: Despite advances in understanding the pathology of septic shock, treatment has not changed for decades and mortality rates remain 10 to 30%. Patients with septic shock are heterogeneous in terms of pathobiology, and our inability to resolve this heterogeneity has contributed to failure of virtually all recent trials of novel therapies. To develop targeted therapies, there is a critical need to understand the biological factors contributing to septic shock heterogeneity. Neutrophils are the primary leukocyte of the innate immune response and play a major role in sepsis pathology. Neutrophil heterogeneity has been considered conceptually, but no subsets have been shown to affect disease outcome. Our objective is to understand how neutrophil heterogeneity contributes to pathobiological differences among patients with septic shock. Olfactomedin 4 (OLFM4) is a neutrophil granule protein that is expressed in 25% of neutrophils in healthy patients. It was recently shown that increase in OLFM4 transcript, soluble OLFM4 in the plasma, and percentage of OLFM4+ neutrophils at the time of presentation to the ICU are associated with poor outcome from septic shock. We have found that, like humans, mice also express OLFM4 in a subset of neutrophils and deletion of OLFM4 from the mouse genome provides protection from death using the cecal ligation and puncture model of septic shock. Therefore we propose to take advantage of the murine model to demonstrate the mechanism of action of OLFM4 in sepsis with the hope to identify novel, targetable pathways for treatment. This proposal will address two important questions: First, understanding the mechanism of action of soluble OLFM4 and OLFM4+ neutrophils by comparing OLFM4 null and wild type mice and the functional characterization of neutrophils that do and do not express OLFM4. Second, we will contribute to the larger field of neutrophil heterogeneity by comparing OLFM4+ and OLFM4- neutrophils in humans and mice. As a career development grant, this program will allow me to build on my background in evolutionary adaptive immunology, to now gain experience in translation, human immunology studies and broaden my immunology training to include innate immunology. The dedicated time for research, the tools and techniques established in the laboratory and the foundation of work combined will allow me to reach my ultimate goal of being an independent RO1 funded primary investigator addressing translation questions in sepsis immunology.